Efficacy of RCC treatment improved thanks to targeted, immune therapies
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Choosing the best treatment for a patient with renal cell carcinoma involves a thorough assessment of the potential advantages and drawbacks of each targeted and immune therapy option based on the patient’s risk level and adjustment based on response to frontline treatment.
The frontline setting for RCC has changed drastically with the development of novel immuno-oncology (IO) therapeutics. Immuno-oncology-based combination strategies have shifted the use of antiangiogenic agents that target the vascular endothelial growth factor (VEGF) pathway such as tyrosine kinase inhibitors (TKIs).
“The large majority of patients are now receiving either IO therapy or IO/TKI therapy in the frontline setting, with TKIs and TKIs plus mTOR inhibitors given in the second and subsequent lines of therapy,” Eric Jonasch, MD, professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, told Healio.
Jonasch noted that although clear cell and non-clear cell RCC are biologically different from one another, treatment guidelines specific to non-clear cell RCC have not been developed. “We acknowledge that this is not ideal, but the algorithms at this point in time are relatively similar for clear and non-clear cell histologies,” he explained.
First-line treatment options
First-line treatment is selected based on patient risk level of good, intermediate or poor. The most common treatments for good risk patients are a combination of axitinib (Inlyta, Pfizer) and pembrolizumab (Keytruda, Merck) or a single-agent, antiangiogenic agent such as sunitinib (Sutent, Pfizer) or pazopanib (Votrient, Novartis). Studies including phase 3 KEYNOTE-426 have shown hazard ratios for overall survival similar for IO-TKI, IO-IO and sunitinib, but Jonasch said the combination therapies have shown a higher complete response rate.
On the other hand, he said, “It’s pretty clear that tumors in these good risk patients are probably more VEGF-driven than those in patients with intermediate or poor risk features. A reasonable consideration for a subset of patients [would be] to start them on an antiangiogenic agent and then use other therapies as a rescue strategy.”
The axitinib-pembrolizumab combination is also a first-line option for intermediate and poor risk patients; others include a combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) or the multitargeted TKI cabozantinib (Cabometyx, Exelixis). Jonasch said this patient population has a more immunologically rich micro-environment. Additionally, due to poor prognosis, Jonasch said these patients “do not do as well with antiangiogenic therapy, and therefore some sort of immune-TKI or IO-IO combination would be more appropriate.”
Treatment choice considerations
An IO therapy approach such as single-agent nivolumab or pembrolizumab is generally well tolerated, Jonasch said. “The downside is if you look at randomized studies or even single-agent studies where single-agent PD-1 blockade has been used, we see that although the objective response rates are decent, progressive disease as best response is fairly high.”
An IO-IO combination such as an ipilimumab-nivolumab offers high complete response rate, but also carries a high rate of serious (grade 3 or higher) toxicities including colitis, hepatitis, nephritis and pneumonitis.
An IO-TKI combination such as axitinib-pembrolizumab typically causes less dangerous toxicities, but potential lifelong discomfort. Jonasch said choosing this route means “relegating an individual to chronic TKI therapy or antiangiogenic therapy, with the chronic, annoying, lower-grade toxicities that are associated with them.” These can include diarrhea, fatigue, hand-foot syndrome, hypertension and loss of taste.
Subsequent, future treatments
For second-line settings and beyond, approved treatments include cabozantinib monotherapy; a combination of lenvatinib and everolimus; and single agent nivolumab. Jonasch said evidence shows a patient on IO-IO therapy will benefit from subsequent TKI therapy. Jonasch referred to an analysis of the phase 2 Study 111/KEYNOTE-146 trial from a presentation at the virtual 2020 ASCO Annual Meeting that showed promising results for the use of a lenvatinib and pembrolizumab combination for patients who were IO refractory.
“It had an objective response rate of 51%, which is quite impressive and a progression-free survival of 11.7 months,” Jonasch said. This shows “that some of these IO-TKI combinations with newer generation TKIs like lenvatinib may actually provide a successful rescue strategy for individuals who have been on prior IO therapy.”
Jonasch also shared an update on future therapies: The oral hypoxia-inducible factor 2-alpha inhibitor MK-6482 could soon be a treatment option for both advanced and hereditary RCC, Jonasch said. This agent is being tested in a phase 3 study against everolimus. Jonasch is lead investigator on a study of MK-6482 for patients with the rare hereditary disorder Hippel-Lindau disease (VHL), as well as VHL-associated RCC.
“This is a promising agent,” Jonasch said.
References:
- Rini BI, et al. J Immunother Cancer. 2019; doi:10.1186/s40425-019-0813-8.
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